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Vol 12 No 2
Research
Melatonin therapy to improve nocturnal sleep in critically ill
patients: encouraging results from a small randomised controlled
trial
Richard S Bourne1, Gary H Mills2 and Cosetta Minelli3
1Sheffield Teaching Hospitals, Critical Care Department, Northern General Hospital, Herries Road, Sheffield, UK, S5 7AU
2Sheffield Teaching Hospitals, Critical Care Directorate, Royal Hallamshire Hospital, Glossop Road, Sheffield, UK, S10 2JF
3Respiratory Epidemiology and Public Health Group, National Heart and Lung Institute, Imperial College London, Emmanuel Kaye Building, Manresa
Road, London, UK, SW3 6LR
Corresponding author: Richard S Bourne, richard.bourne@sth.nhs.uk
Received: 8 Feb 2008 Revisions requested: 13 Mar 2008 Revisions received: 11 Apr 2008 Accepted: 18 Apr 2008 Published: 18 Apr 2008
Critical Care 2008, 12:R52 (doi:10.1186/cc6871)
This article is online at: http://ccforum.com/content/12/2/R52
© 2008 Bourne et al.; licensee BioMed Central Ltd.
This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Introduction Sleep disturbances are common in critically ill
patients and when sleep does occur it traverses the day-night
periods. The reduction in plasma melatonin levels and loss of
circadian rhythm observed in critically ill patients receiving
mechanical ventilation may contribute to this irregular sleep-
wake pattern. We sought to evaluate the effect of exogenous
melatonin on nocturnal sleep quantity in these patients and,
furthermore, to describe the kinetics of melatonin after oral
administration in this patient population, thereby guiding future
dosing schedules.
Methods We conducted a randomised double-blind placebo-
controlled trial in 24 patients who had undergone a
tracheostomy to aid weaning from mechanical ventilation. Oral
melatonin 10 mg or placebo was administered at 9 p.m. for four
nights. Nocturnal sleep was monitored using the bispectral
index (BIS) and was expressed in terms of sleep efficiency index
(SEI) and area under the curve (AUC). Secondary endpoints
were SEI measured by actigraphy and nurse and patient
assessments. Plasma melatonin concentrations were measured
in nine patients in the melatonin group on the first night.
Results Nocturnal sleep time was 2.5 hours in the placebo
group (mean SEI = 0.26, 95% confidence interval [CI] 0.17 to
0.36). Melatonin use was associated with a 1-hour increase in
nocturnal sleep (SEI difference = 0.12, 95% CI -0.02 to 0.27; P
= 0.09) and a decrease in BIS AUC indicating 'better' sleep
(AUC difference = -54.23, 95% CI -104.47 to -3.98; P = 0.04).
Results from the additional sleep measurement methods were
inconclusive. Melatonin appeared to be rapidly absorbed from
the oral solution, producing higher plasma concentrations
relative to similar doses reported in healthy individuals. Plasma
concentrations declined biexponentially, but morning (8 a.m.)
plasma levels remained supraphysiological.
Conclusion In our patients, nocturnal sleep quantity was
severely compromised and melatonin use was associated with
increased nocturnal sleep efficiency. Although these promising
findings need to be confirmed by a larger randomised clinical
trial, they do suggest a possible future role for melatonin in the
routine care of critically ill patients. Our pharmacokinetic
analysis suggests that the 10-mg dose used in this study is too
high in these patients and may lead to carryover of effects into
the next morning. Reduced doses of 1 to 2 mg could be used in
future studies.
Trial registration Current Controlled Trials ISRCTN47578325.
Introduction
Sleep disturbances are common in critically ill patients, who
present a loss of monophasic nocturnal sleep combined with
frequent diurnal naps (irregular sleep-wake pattern) [1] as well
as a reduction in deeper, more restorative phases such as
slow-wave sleep (SWS) and rapid eye movement (REM) sleep
[2]. Although the consequences of such prolonged sleep frag-
mentation are unknown, they may be comparable to the signif-
AUC = area under the curve; AUC(0–24) = area under the concentration time curve between time 0 and 24 hours; BIS = bispectral index; Cmax =
maximum plasma concentration; CYP1A2 = cytochrome P450 1A2; EEG = electroencephalogram; ICU = intensive care unit; RCSQ = Richards
Campbell Sleep Questionnaire; REM = rapid eye movement; SAS = Sedation Agitation Scale; SD = standard deviation; SEI = sleep efficiency index;
SWS = slow-wave sleep.
Critical Care Vol 12 No 2 Bourne et al.
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icant morbidity associated with prolonged sleep deprivation
[3]. Patients themselves perceive sleep disturbances to be
one of the most stressful components of their intensive care
stay [4].
Nocturnal secretion of melatonin synchronises the sleep-wake
and dark-light cycles [5], and disruption to the normal timing
and amplitude of the circadian rhythm of melatonin secretion
is associated with reduced sleep [6,7]. Reduction in plasma
melatonin levels and lack of circadian rhythm have been shown
in critical care patients undergoing mechanical ventilation [8-
11].
Exogenous melatonin has been demonstrated to be safe and
effective in the treatment of other circadian rhythm sleep dis-
orders [12]. This study aimed to examine the effect of exoge-
nous melatonin on nocturnal sleep in patients being weaned
from mechanical ventilation. The optimum oral dose to use in
this population is also unknown and therefore a pharmacoki-
netic analysis of plasma melatonin concentrations was also
undertaken.
Materials and methods
We conducted a randomised double-blind placebo-controlled
trial in patients admitted to an adult general intensive care unit
(ICU) with acute respiratory failure requiring mechanical venti-
lation and tracheostomy to assist weaning. Exclusion criteria
were an expected ICU length of stay of less than 5 days, pre-
admission treatment of sleep disturbances, contraindications
to enteral feeding, a history of convulsions, psychiatric or neu-
rological disease, alcohol consumption of greater than or
equal to 50 units per week or drug use, sleep apnoea, severe
heart failure (New York Heart Association classification III/IV),
and low levels of consciousness, defined as values of below 4
on the Sedation Agitation Scale (SAS) [13]. The local ethics
committee approved the study protocol and all patients pro-
vided written informed consent.
Patients were randomly assigned to melatonin or placebo by
the pharmacy, using random assignment in blocks of four.
Melatonin 10 mg, formulated in an oral liquid, or matching pla-
cebo was administered enterally at 9 p.m. for four consecutive
nights [14]. Propofol and alfentanil were discontinued at least
30 hours, and morphine and midazolam at least 48 hours,
before study entry. No hypnotics were allowed during the
study. Haloperidol was allowed in very agitated patients (SAS
of greater than or equal to 6). Earplugs and eye masks were
made available for use at the patients' discretion, and staff
meetings and posters were employed to encourage staff to
minimise environmental, nursing, and clinical disturbances
during the nocturnal study periods. Environmental distur-
bances were documented based on a locally derived scale
composed of light interruptions, clinical activities, and use of
invasive instrumentation (Additional file 1). The nurses also
subjectively ranked the noise level each night (Additional file
1). Baseline nocturnal illuminance at the head of each patient
bed when all lights were off was recorded using a light meter
(Luxmeter PU150; Eagle International, Wembley, UK). Drug
records were compiled daily for drugs known to adversely
affect sleep [15] or melatonin pharmacokinetics [16].
Sleep measurement
Nocturnal sleep was evaluated using the bispectral index
(BIS) (BIS XP, Quattro sensor; Aspect Medical Systems, Inc.,
Norwood, MA, USA), a signal-processing technique based on
the electroencephalogram (EEG) previously used to evaluate
sleep in critical care patients [17]. BIS data were recorded in
5-second intervals and downloaded onto a personal compu-
ter. Two outcome measures were used: sleep efficiency index
(SEI) and area under the curve (AUC). SEI was defined as the
ratio of a patient's total sleep time over the time available for
'nocturnal' sleep (9 hours, from 10 p.m. to 7 a.m., correspond-
ing to nursing staff shift patterns). Sleep was defined as BIS
below 80 [18]. AUC was calculated using the trapezoidal rule,
which uses trapeziums to approximate the region under a
curve and calculate its area. For each night, SEI and AUC val-
ues were set to missing if recordings were missing for more
than 2 hours. Analyses were limited to nights 3 and 4 since the
potential chronohypnotic benefits of melatonin are not imme-
diate and may take 3 days to be realised [19,20]. All four
nights were considered in a secondary analysis.
During the study, other sleep measurement methods were
used with the main aim of evaluating agreement and compar-
ing feasibility and reliability in the critical care setting. These
included actigraphy (Actiwatch; Cambridge Neurotechnology
Ltd., Cambridge, UK), nurse assessment (direct nurse obser-
vation using hourly epochs), and patient assessment (Rich-
ards Campbell Sleep Questionnaire [RCSQ]). Details of the
methods and results on measurement agreement are reported
elsewhere [21]. Results of these methods for the melatonin
effect, expressed in terms of SEI, are reported here as second-
ary analyses.
Statistical analysis
Differences between treatment groups in mean values of SEI
and AUC, averaged over nights 3 and 4, were analysed using
the t test with equal variances. For the secondary analysis,
including all four nights, we used a multilevel model, Prais
regression, which accounts for the within-patient correlation
between measurements on successive nights. Mean and
standard deviation (SD) or median and interquartile range
were used as appropriate for descriptive statistics. The Pear-
son correlation was used for test of association. Data were
analysed using Stata 9.1 software (StataCorp LP, College
Station, TX, USA).
A sample size of 34 patients was calculated based on BIS SEI,
assuming α = 0.05, power = 0.8, and minimum detectable dif-
ference in SEI = 0.20. Since no data on the SD of BIS SEI in
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critical care patients were available, we used the SD of SEI
obtained using polysomnography as a proxy. Polysomnogra-
phy studies reported SD values from 0.1 to 0.24 [2,22-24]
and we used a conservative value of 0.20.
Pharmacokinetic analysis
Pharmacokinetic analysis of plasma melatonin concentrations
was undertaken in the first nine patients in the melatonin
group. Twelve blood samples were collected from each
patient at appropriately spaced intervals after the first oral
dose. All samples were taken from the arterial line, immediately
centrifuged, and stored at -20°C until assay. Plasma melatonin
was measured in duplicate using a melatonin direct radioim-
munoassay (Immuno Biological Laboratories, Hamburg, Ger-
many). Sample dilution to within the linear range of the assay
was undertaken as necessary. The values of intra-assay preci-
sion (percentage coefficient of variation) at plasma concentra-
tions of approximately 10 and 150 pg/mL were 13.6% and
6.8%, respectively. The interassay coefficient of variation was
24.5%. Plasma concentrations were corrected for endog-
enous plasma melatonin concentration by subtracting the 9
p.m. baseline value. Non-compartmental pharmacokinetic
analysis was undertaken (PKSolution 2.0; Summit Research
Services, Montrose, CO, USA).
Results
Figure 1 shows patients' inclusion in the study. Due to slow
recruitment, we could recruit only 24 patients. There were 4
patients (3 in the placebo and 1 in the melatonin group) with
missing data for nights 3 and 4, the reasons being discharged/
re-sedated (4 nights), patient removed sensor (2 nights), sig-
nal quality index low (1 night), and patient refused (1 night).
Table 1 shows patients' baseline characteristics in the two
treatment groups. An imbalance of known risk factors for sleep
disturbances was present due to small sample size, potentially
leading to more sleep disturbance in the melatonin group.
Such factors included older age [25], delirium [26], and venti-
lation with pressure support ventilation (because of the possi-
bility of desynchrony) [27]. No differences between the
melatonin and control groups were observed with regard to
either patient uptake of earplugs or eye masks (9% and 2% of
nights, respectively) or nocturnal environmental disturbances
score. The mean (SD) baseline illuminance at the head of each
Figure 1
Flowchart of the study, from patient recruitment to analysisFlowchart of the study, from patient recruitment to analysis.
Critical Care Vol 12 No 2 Bourne et al.
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bed when all lights were turned off was 9.6 (2.6) lux.
There was no disparity between the groups in their exposure
to the number of potentially sleep-disruptive medications. In
patients who received morphine and midazolam, sufficient
time elapsed between discontinuation of sedation and study
enrolment to limit the potential distortion of results due to
accumulation of these agents. None of the patients received
haloperidol on nights 3 or 4. Nocturnal sleep time did not
seem to correlate with patients' severity of illness, as meas-
ured by APACHE II (Acute Physiological and Chronic Health
Evaluation II) daily score, although the wide confidence interval
does not allow us to draw definitive conclusions (r = 0.10; -
0.36 to 0.52; P = 0.68).
Results of the effect of melatonin on primary and secondary
sleep measurements are shown in Table 2. Nocturnal sleep
time was 2.5 hours in the placebo group and was 1 hour
longer in the melatonin group, although the difference was not
statistically significant (Table 2). BIS AUC showed a statisti-
cally significant 7% decrease in the melatonin group, with
lower AUC meaning 'better' sleep (AUC difference = -54.23;
-104.47 to -3.98; P = 0.04). To account for the imbalance in
baseline characteristics, we adjusted the analyses using linear
regression. The small sample size limited the number of covari-
ates we could adjust for [28] and we thus created a single var-
iable indicating the overall baseline risk of sleep disturbances.
High risk was defined as the presence of any two of the follow-
ing: age of greater than or equal to 70 years, delirium positive,
and ventilation with BiPAP (biphasic positive airway pressure)
or CPAP-ASB (continuous positive airway pressure with
assisted spontaneous breathing). The results of the adjusted
analysis did not vary substantially, apart from an expected loss
in precision of the estimates: SEI difference = 0.12 (-0.04 to
0.28; P = 0.12) and AUC difference = -48.76 (-103.06 to
5.54; P = 0.07). Any evidence of a treatment effect nearly dis-
appeared when considering all four nights: SEI difference =
0.05 (-0.07 to 0.17) and AUC difference = -26.62 (-70.51 to
17.28). Results from the additional sleep measurement meth-
ods did not support those obtained with BIS and indeed were
all inconclusive (Table 2). As regards possible side effects of
melatonin, one patient in the melatonin group reported a head-
ache on a single night, which responded to acetaminophen
administration.
Table 1
Baseline patient characteristics
Characteristic Placebo (n = 12) Melatonin (n = 12)
Male, number (percentage) 7 (58.3) 4 (33.3)
Reason for ICU admission, number (percentage)
Severe sepsis 8 (66.7) 10 (83.3)
Postoperative respiratory failure 2 (16.7) 1 (8.3)
Pneumonia 2 (16.7) 1 (8.3)
Age in years, mean (SD) 58.7 (12.5) 69.9 (12.0)
APACHE II score on study entry, mean (SD) 16.8 (3.4) 17.3 (3.8)
Actual body weight in kilograms, median (IQR) 69.0 (57.4; 77.5) 65.0 (63.5; 70.0)
Ideal body weight in kilograms, mean (SD) 60.0 (6.9) 57.2 (6.5)
Body mass index, mean (SD) 24.6 (4.7) 25.0 (3.1)
Patients' usual sleep quantity in hoursa, mean (SD) 6.5 (1.57) 6.2 (2.07)
ICU length of stay prior to study in days, median (IQR) 16.5 (13.0; 20.5) 16.5 (11.0; 19.0)
Time of ventilation prior to study in days, mean (SD) 20.0 (14.3) 13.6 (6.5)
Sedation (morphine/midazolam) prior to study, number (percentage) 2 (16.7) 2 (16.7)
Time since sedation stopped prior to study in days, mean (SD) 6.6 (2.9) 7.5 (4.7)
Delirium during study period, number (percentage) 1 (8.3) 4 (33.3)
Ventilation mode on nights 3 and 4, number (percentage)
BiPAP/CPAP-ASB 7 (70.0) 7 (58.3)
External CPAP/Hi-flow oxygen 3 (30.0) 5 (41.7)
aUsual sleep time at home as reported by the patient. APACHE II, Acute Physiological and Chronic Health Evaluation II; BiPAP, biphasic positive
airway pressure; CPAP, continuous positive airway pressure; CPAP-ASB, continuous positive airway pressure with assisted spontaneous
breathing; ICU, intensive care unit; IQR, interquartile range; SD, standard deviation.
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The main pharmacokinetic data are summarised in Table 3.
Plasma melatonin concentrations declined bi-exponentially
(Figure 2). Both maximum plasma concentration (Cmax) and
AUC(0–24) (area under the concentration time curve between
time 0 and 24 hours) had a moderately strong correlation with
plasma alanine transaminase concentrations (r = 0.70; 0.06 to
0.93; P = 0.04, and r = 0.62; -0.07 to 0.91; P = 0.07, respec-
tively). No such association was found with age, gender,
weight, creatinine, or bilirubin. No association was found
between the pharmacokinetic parameters: Cmax, AUC(0–24) or
C(08) (plasma concentration at 8 a.m.), and mean SEI or BIS
AUC measurements of nocturnal sleep.
Discussion
Our study confirms previous findings [17,29] that nocturnal
sleep in patients being weaned from mechanical ventilation is
highly compromised, with an average of only 2.5 hours in the
placebo group. Melatonin therapy was associated with a 1-
hour increase in nocturnal sleep compared with placebo, cor-
responding to an increase of 47%, although the SEI difference
did not reach statistical significance. We found a statistically
significant reduction of 7% in BIS AUC with melatonin admin-
istration, suggesting sleep improvement. The use of AUC has
some advantages compared with SEI. Apart from providing
greater statistical power, BIS AUC provides an indication of
both sleep quantity and quality [17], which might be more
informative than sleep quantity alone. However, the clinical sig-
nificance and interpretation of a reduced AUC remain unclear
[30].
Two other small trials investigated the effect of melatonin on
nocturnal sleep in critically ill patients [11,31], but comparison
is limited due to the use of different sleep measurement meth-
ods, for which agreement is rather poor [21]. In fact, although
polysomnography is the gold standard for quantifying and
qualifying sleep, the challenges of the critical care environment
have led to the use of a number of alternative methods [21].
The first study was a crossover trial that used actigraphy on
eight respiratory patients and showed positive results [31].
Baseline sleep was reported to increase from approximately 3
to 6 hours with melatonin administration, although results of
the comparison between melatonin and placebo were not
reported. The second study used nurse observation to evalu-
ate 32 tracheostomised patients and showed negative results
[11]. Placebo patients slept for about 4 hours, with only 15
minutes more in the melatonin group. As a measure of sleep,
actigraphy is not ideal in critically ill patients, being influenced
by abnormalities of the neuromuscular system which are com-
mon in these patients [21]. As regards nurse observation,
intensive observation of sleep (5-minute intervals) is probably
necessary to allow differentiation between interventions in crit-
ical care studies [32] and even then it suffers from being a sub-
jective measure that may overestimate sleep quantity [33].
Patient assessment has been used in critical care sleep stud-
ies on other interventions but its applicability is limited by
patients' acute cognitive and perceptual problems [21]. We
chose to use BIS as the primary outcome measure since it pro-
Table 2
Effect of melatonin on nocturnal sleep efficiency on nights 3 and 4, using different outcome measures
Bispectral index sleep efficiency index (95% confidence interval)
Sleep measurement method Placebo group Melatonin group Difference P value of the difference
Primary analysis
Bispectral index 0.26 (0.17 to 0.36) 0.39 (0.27 to 0.51) 0.12 (-0.02 to 0.27) 0.09
Secondary analysis
Actigraphy 0.75 (0.67 to 0.83) 0.73 (0.53 to 0.93) -0.02 (-0.24 to 0.20) 0.84
Nurse assessment 0.51 (0.35 to 0.68) 0.45 (0.26 to 0.64) -0.06 (-0.29 to 0.17) 0.58
Patient assessment (RCSQ) 0.50 (0.43 to 0.58) 0.41 (0.24 to 0.59) -0.09 (-0.28 to 0.09) 0.32
RCSQ, Richards Campbell Sleep Questionnaire.
Figure 2
Semi-logarithmic plot of mean melatonin plasma concentration (± standard deviation [± SD]) versus clock time after a 10-mg oral solution dose administered at 9 p.m. in critical care patientsSemi-logarithmic plot of mean melatonin plasma concentration (±
standard deviation [± SD]) versus clock time after a 10-mg oral solution
dose administered at 9 p.m. in critical care patients. *4 a.m. data point.
Mean concentration value minus SD is a negative number and cannot
be represented on a logarithmic scale.